The present invention relates to a process for the industrial synthesis of perindopril of formula (I): 
and pharmaceutically acceptable salts thereof.
Perindopril, and also pharmaceutically acceptable salts thereof, and more especially the tert-butylamine salt thereof, have valuable pharmacological properties. Their principal property lies in the inhibition of the enzyme that converts angiotensin I (or kininase II), which enables on the one hand prevention of the conversion of the decapeptide angiotensin I to the octapeptide angiotensin II (vasoconstrictor) and on the other hand prevention of the degradation of bradykinin (vasodilator) to inactive peptide. Those two actions contribute to the beneficial effects of perindopril in cardiovascular disorders, especially arterial hypertension and cardiac insufficiency.
Perindopril, its preparation and its therapeutic use have been described in European Patent Specification EP 0 049 658.
Given the pharmaceutical interest in that compound, it is important to be able to obtain it by an effective industrial synthesising process that can readily be applied on an industrial scale, yielding perindopril in a good yield and, especially, with an excellent degree of purity.
The Patent Specification EP 0 308 341 describes the industrial synthesis of perindopril by the coupling of (2S,3aS,7aS)-octahydroindole-2-carboxylic acid benzyl ester with N-[(S)-1-carboxybutyl]-(S)-alanine ethyl ester, followed by deprotection of the carboxylic group of the heterocycle by catalytic hydrogenation. That process has the advantage of yielding perindopril in a good yield from starting materials for which industrial synthesis has already been described. However, the purity of the perindopril obtained by that process is not satisfactory, and necessitates a purification step in order to obtain perindopril of a quality that would allow its use as a pharmaceutical active ingredient. Indeed, under the conditions described in that patent specification the perindopril obtained is contaminated by significant amounts of the impurities of formulae (II) and (III) 
The Applicant has now developed a new industrial synthesising process that yields perindopril in a degree of purity that is compatible with its use as a pharmaceutical active ingredient, the levels of impurities of formulae (II) and (III) being less than 0.2% and 0.1%, respectively.
More specifically, the present invention relates to a process for the industrial synthesis of perindopril which is characterised in that the benzyl ester of formula (IV): 
wherein Bn represents the benzyl group, is reacted with the compound of formula (V): 
in ethyl acetate, in the presence of an amount of from 0.4 to 0.6 mol of 1-hydroxybenzotriazole per mol of compound of formula (IV) employed and in the presence of an amount of from 1 to 1.2 mol of dicyclohexylcarbodiimide per mol of compound of formula (IV) employed, in the absence of triethylamine or in the presence of an amount of triethylamine that is less than or equal to 1 mol per mol of compound of formula (IV) employed, preferably less than or equal to 0.25 mol per mol of compound of formula (IV) employed, at a temperature of from 20 to 77xc2x0 C., to yield, after isolation, the compound of formula (VI): 
wherein Bn represents the benzyl group, the carboxylic group of the heterocycle of which is deprotected by catalytic hydrogenation to yield perindopril of formula (I), which is converted, if desired, into a pharmaceutically acceptable salt, such as the tert-butylamine salt.
The process is of particular interest for the following reasons:
The coupling in alkaline medium of the benzyl ester of formula (IV) with the compound of formula (V) has been described in the Patent Specification EP 0 308 341. But, under the conditions described (the use of 3 mols of compound of formula (V), 3 mol of triethylamine, 3.8 mol of 1-hydroxybenzotriazole and 2.9 mol of dicyclohexylcarbodiimide per mol of compound of formula (IV) employed), numerous secondary products are formed. In particular, the compound of formula (VI) obtained contains in significant amounts (5 to 15%) the impurities of formulae (VII) and (VIII) which, when debenzylation is carried out, result in the impurities of formulae (II) and (III) 
The Applicant has found, unexpectedly, that the reduction, or even omission, of triethylamine in the coupling step, has made it possible to restrict the levels of impurities of formulae (VII) and (VIII) in the compound of formula (VI) to less than 1.5%.
The catalytic hydrogenation of the compound of formula (VI) so obtained yields perindopril of far better purity, and in particular with levels of impurities of formulae (II) and (III) of less than 0.2% and 0.1%, respectively.
In addition, the reduction, in the coupling step, of the amount of compound of formula (V), of 1-hydroxybenzotriazole and of dicyclohexylcarbodiimide, enables a yield of compound of formula (VI) to be obtained that is as good as that obtained with larger amounts of reagents, thus making the process far more advantageous on an industrial scale.
The Examples below illustrate the invention but do not limit it in any way.